In spite of intensive investigations in many laboratories, both the etiology and pathogenetic mechanisms leading to multiple sclerosis remain unsolved. Among several unexplained immunological observations has been the observation that circulating immune complexes have been noted in these patients and that elevated levels of circulating complexes are noted in the CSF of these patients during acute exacerbations of the disease. However, neither the nature of the antigen(s) nor their role in the disease process is known. Encouraged by our prior success in detecting streptococcal antigens within circulating complexes we have embarked on a study of possible antigen(s) within immune complexes which have been checked for specificity by the raji cell method and then injected into rabbits. The rabbit anti-immune complex sera were tested by either cross immunoelectrophoresis (CIE) or immunoblotting procedures against brain extracts solubilized from either M.S. or non-M.S. autopsy brain material. Our results indicate that M.S. immune complexes do contain brain antigens which are present in both M.S. and non-M.S. brain. In addition, these antigens appear to be cross-reactive with certain components of measles virus. Control sera made against non-M.S. complexes were non-reactive to brain extracts indicating that these sera were not reacting just to serum protein present in brain extracts. Absorption studies with mononuclear cell populations as well as cytotoxicity testing of these antibodies indicated that these antibodies are not directed against lymphocytic or platelet antigens. Our plan is now to further identify and purify the brain antigen(s) using both the CIE and ELISA techniques as well as affinity studies. The second phase will be to determine what is the measles viral antigen which is cross-reactive with the brain antigen(s). Finally, we will look for antibodies in both serum and CSF samples of M.S. patients to see if these antibodies are directed towards brain antigens similar to those found in the complexes and whether they fluctuate during disease periods. A corollary study will be to determine whether there is cellular reactivity to these brain antigens in M.S. patients.